Cyclohexylsulfamylbenzoic acid



Patented Aug. 26, 1952 2,608,512 CYCLOHEXYLSULFAMYLBENZOIG hem Charles S. Miller, Prosp ect Park, Pa., assignor to Sharp & Dohme, Incorporated, Philadelphia, Pa., a corporation of Maryland No Drawing. Original application August 21), 1949, Serial No. 111,584. Divided and thisapplication June 28, 1950, Serial No. 170,939

2 Claims.

This invention relates to a new compound which is effective as an adjuvant for use in conjunction with the administration of penicillin to provide an increase in the bloodplasmapenicillin concentration with a given dose of penicillin, thereby making possible very high penicillin blood levels, or permitting the use of smaller quantities of penicillin for providing a given blood level, or permitting the less frequent administration'of penicillin while maintaining a penicillin bloodlevel adequate for bactericidal or bacteriostatic purposes. The invention also relates to the preparation or various dosage forms in which this new compound is incorporated ,for administration by various routes.

Penicillin appears to be almost quantitatively excreted from the, bloodby the epithelial cells .of the tubules, at least within plasma concentrations which have been explored, with the result that its rate of excretion from the blood stream is approximately five times that of materials whichareexcreted by glomerular filtration alone, the tubular excretion accounting for about 80 (811% and the glomeruli about20 (195%.

Various proposals havebeen made-to overcome the difficulties due to the rapid elimination of penicillin, such as the administration of it in suspension in an oleaginousmateriahthemixture being administered by intramuscular injection. A second proposal which has been made has been to use a material such as diodrastor para-aminohippuric acid which, like penicillin,isselectively excreted by the tubules. Neither oi-these proposals has afforded a satisfactory solution to the problem, since the useof an oleaginous suspension of penicillin merely prolongs the time interval between injections and does not provide a high blood level of penicillinand, while the second proposal provides a means-to inh-ibitthe excretion of penicillin by the kidney tubules-to a substantial extent, it does so at the expense of overloading the tubules with materials which they function to remove from the blood.

The present invention is basedupon the discovery that removal of penicillin'from the blood stream by the kidney tubules canbeceffectively blocked by the new adjuvant of this invention, para-(cyclohexylsulfamyl) -benzoic acid, having the general formula 1 and its salts. l

The new sulfamyl henzoic acid of the invention is generally made by first preparing a-paracarboxybenzenesulfonyl halide by oxidation of para-toluenesulionyl halide, or by preparing para-cyanobenzenesulfony1. halide by treating para-sulfamyl benz oic acid with phosphorus pentachloride. The para-carboxybenzenesulionyl halide or para-cyanobenzenesulfonyl halide thus formed is reacted with the cyclohexylamine, ad'- vantageously using an excess, for example; two to threeeguivalents, of the. amine, and Iwhenthe cyanobenzenesulfonyl halide reactant is used, hydrolyzing the product thus .fprmed to the cor responding carboxyl derivative. The reaction is preferably carried out inthe presence of .asol vent, such as acetne or pyridine and. the like, or in aqueous sodium hydroxide, and preferably with cooling. Any by-product.formedduringthe reaction is removed. by treating the reaction medium with a weak, alkaline substance, such as an aqueous sodium bicarbonate solution, filtering off the (precipitated. by-product, and then recov ering the para- (cyclohexylsiilfamyli benzoic acid iromthe filtrate by acidification. M

The preparation of theneWlCQj. Founder the invention is illustrated by, but not restrictedlto the folloyving examplef Few .-;icyc cflwa su mm l .bww a ial-{E0 r ms Q-3mc21 -1o l y lehfir lemm 1i l es i .20aca;e ecetqretwntained in were, a k :pm id d h a; st 1 1' 2 05 en ma- 0.1 mo o h r af e er s was added in portions w The .r e e ifln w fa wh ch t q de1 T then added asvwell a Y nd z t sipiie a The crude product thus-obtained w in a odium bicarbonate.

w -wer an ;hour dur ng 3 of the purified product, melting at 259-260", was obtained.

The para-(cyclohexylsulfamyl) -benzoic acid of this invention is relatively non-toxic, it is soluble in blood plasma and operates, when carried by the blood stream into contact with the tubules, to prevent their normal action in removing penicillin from the blood stream. The adjuvant itself is not excreted to any substantial extent by the tubules, and the available evidence indicates that on coming into contact with the epithelial cells of the tubules, it operates to block their action by interference with the normal functioning of the epithelial cells and does not inhibit the excretion of the penicillin by competing with it within the tubular functional capacity. Thus,

the adjuvant is effective in eliminating Or very radically reducing tubular excretion of penicillin.

in plasma concentrations around mg. per 100 cc., which is about the threshold value for agents such as p-aminohippuric acid or diodrast. The highly efiective adjuvant of this invention will reduce the excretion of penicillin by the tubules, at a blood plasma concentration of about 10 mg. per 100 cc. to almost zero, so that the actual elimination of penicillinffrom the blood stream becomes substantially that resulting from glomerular filtration, that is, about one-fifth the normal rate (ignoring plasma binding). The adjuvant itself is eliminated by the glomeruli.

I The adjuvant can be administered orally or, when dissolved in an aqueous solution, it can be administered intravenously or intramuscularly, and in either case, in admixture with penicillin or separately therefrom.

Whether the adjuvant is administered in admixture with or separately from the penicillin, the quantity used should be such as to provide a concentration in theblood stream of adjuvant adequate to block substantially the excretory mechanism of the tubules. Maximum effect will be obtained with blood plasma concentrations of about 5 to mg. per 100 cc., obtainable at dosage levels of about 4 to '16 grams per day orally and somewhat less than this intravenously. In a composition comprising both penicillin and the adjuvant, a ratio of about 0.5 gram of adjuvant to from 25,000 to 200,000 units of penicillin is advantageous.

In general, oral administration of the adjuvant at the rate of 4 to 16 grams per day is adequate to suppress the rate of penicillin excretion to an extent such that the blood level with a given dose of penicillin administered orally or intramuscularly in aqueous solution will be increased to as much as four times the level obtained without the use of the adiuvant.

The 'adjuvant may be prepared in any convenient dosage form, either alone or admixed with penicillin, such as in a compressed tablet, a dry filled capsule or a soft elastic capsule. It is to be understood, of course, that other ingredients, such as binders, diluents, excipients, antacid substances, Or other inert or therapeutically active compounds may be incorporated into any selected dosage form along with the adjuvant or adjuvant plus penicillin, provided the added ingredient does not destroy the activity of either the adjuvant or penicillin. Similarly, the adjuvant and, if desired, th penicillin may be dispersed in an oleaginous base either alone or along with other suitable substances and filled into soft elastic capsules or an aqueous solution may be prepared and filled into ampuls. Other suitable dosage forms will be readily apparent to those skilled in the art, and it is not the purpose of this discussion to limit the mode of packaging or administration to the example specifically described below.

Compressed tablets Part 1.-4,54=8 grams of corn starch are hydrolyzed with 40 liters of hot water. 50,000 grams of para-(cyclohexylsulfamyl) -benzoic acid are added to the wet paste and the entire mass is then granulated. The wet granulated material is passed through a coarse screen, spread thinly on trays and dried in an oven at about 60 C. for 24 hours and then passed through a No. 14 screen.

Part 2.-l31 grams of ethyl cellulose (having a low viscosity, e. g., 20 centipoises) are dissolved in 3.5 liters of anhydrous alcohol with the aid of gentle heating and in an atmosphere controlled at 30% relative humidity at 25 C. In a separate container, 6,666 grams of penicillin G sodium, 5,425 grams of powdered sodium bicarbonate and 1,618 grams of dried corn starch are intimately mixed together and then passed through a line screen. This mixed powder is granulated with the warm solution of ethyl cellulose, adding additional anhydrous alcohol, if necessary, to form good granules. The granulated material is passed through a coarse screen, spread on trays and dried in an oven at 55 C. for'l l hours and then passed through a No. 20 screen.

I The granules obtained in Part 1 andPart 2 are combined and mixed with 4,927 grams of granular sodium bicarbonate and then 6,660 grams of dried corn starch are intimately mixed therein. After thorough stirring, 7,000 grams of dried talc and 525 grams of magnesium stearate are added and the mixture again thoroughly stirred. This final mixture is compressed into tablets using a onehalf inch die and flat face, double edge punches yielding 100,000 tablets each weighing 0.875 gram and containing 0.5 gram of para-(cyclohexylsulfamyD-benzoic acid and 100,000 units (plus 10% excess) of penicillin G sodium.

In compositions containing penicillin, it is advisable, in accordance with customary practice, to include an excess of the penicillin, for example, a ten per cent excess over the label-claimed quantity in accordance with present practice. An excess of penicillin" introduces no difiiculty save its cost. The penicillin used may be any of the forms available for use, such as the calcium, sodium, potassium, procaine, and the like salts of amorphous or crystalline penicillin.

Having now particularly described the invention, what is claimed is:

1. An adjuvant which is a member of the group consisting of para-(cyclohexylsulfamyl) -benzoic acid, having the formula N-SOz COOH and its non-toxic, water-soluble'salts.

2. A composition suitable for therapeutic use,

, comprising penicillin and an a'djuvant which is a member of' the group consisting of para- (cyclohexylsulfamyl)-benzoic 'acid, having the formula H t i N-SQ1+=COCH and its non-toxic, water-soluble 'salts,the quan- 5 tity of adjuvant and penicillin in the composition being in the ratio of 0.5 gram of, adjuvant to from 25,000 to 200,000 units of penicillin.

CHARLES S. MILLER.

REFERENCES CITED The following references are of record in the file of this patent:

Reid: Prolongation of Penicillin Activity with Penicillinase-Inhibiting Compounds. Proc. Soc. Exptl. Biol. and Med., Nov. 1946, pages 438 to 443. 167/65P.

Soc-H00: Activity of Penicillin Combined with Other Anti-Streptococcal Agents Archives Biochemistry. :Sept. 1944, pages 99 to 106.

Meads: Caronamide and Penicillin. J. Am. Med. Assoc, Nov. 20, 1948, pages 874 to 877. 167/65P.

Pratt et a1.: Antibiotics Lippincott; Company, 1949, pages 112 to 116. (Book in Division 43.)

Ruggli et a1.: Chem. Abstracts, volume 35, column 5473-4 (1941).

Gilman et a1.: J. Am. Chem. $00., volume 69, pages 1537-8 (1947). (Copies in Sci. Library.) 

2. A COMPOSITION SUITABLE FOR THERAPEUTIC USE, COMPRISING PENICILLIN AND ADJUVANT WHICH IS A MEMBER OF THE GROUP CONSISTING OF PARA(CYCLOHEXYLSULFAMYL)-BENZOIC ACID, HAVING THE FORMULA 